Use of Botulinum toxin A (botox) to treat depression and its effect on fight/flight repsonse

Question

Over in Health.SE, @faustus provided a couple of references to papers which suggest the use of Botulinum toxin A (BTA) - otherwise known as botox - to treat depression — Magid, et al. (2015a) and Finzi & Rosenthal, (2016)

Magid, et al. (2015a) states that

a single treatment of BTA in the glabellar region can produce a strong reduction in the symptoms of major depression

^{Figure: Improvement in BDI score. The figure shows absolute reduction in the BDI scores (14.3 vs. 5.1±standard error of the mean) from the baseline to the primary end point 6 weeks thereafter in the combined sample (n=134) for the BTA (n=59) and the placebo group (n=75), respectively.}

whilst Finzi & Rosenthal, (2016) states that

In an initial case series, one of us (EF) injected BT into the frown of ten depressed patients, eight of whom went into remission after one treatment (Finzi and Wasserman, 2006; Finzi, 2013). The study was limited by its small size, lack of controls, and lack of blinding. In three subsequent randomized, double blind and placebo controlled trials, we and other researchers have found response rates of 50—60% in major depression, with about one third of patients going into remission (Wollmer et al. 2012; Finzi and Rosenthal, 2014; Magid et al. 2014, 2015b). BT showed antidepressant effects both when used as an ancillary treatment and by itself.

However, they then go on to say

How might injecting BT into the corrugator muscle influence the emotional brain? FMRI imaging has shown that subjects who received BT injections into their frown muscles had amygdala that were less responsive to negative stimuli (Hennenlotter et al. 2009). Recent work has confirmed that amygdala activity in response to angry faces was decreased when the frown muscles were paralyzed by BT injection. Furthermore, amygdala activity returned to its original inducible state after the effects of the BT injection had worn off, confirming that BT reversibly severed afferent feedback from the corrugator muscle to the amygdala (Kim et al. 2014).

With the decrease in amygdala activity in response to angry faces, am I correct in thinking that this could have a detrimental effect with regard to the flight/flight response in potentially dangerous situations?

References

Finzi, E. (2013). Antidepressant effects of botulinum toxin A: scientific rationale. Journal of psychiatry & neuroscience: JPN, 38(5), E29. PMCID: PMC3756121

Finzi, E., & Rosenthal, N. E. (2014). Treatment of depression with onabotulinumtoxinA: a randomized, double-blind, placebo controlled trial. Journal of psychiatric research, 52, 1-6. DOI: 10.1016/j.jpsychires.2013.11.006

Finzi, E., & Rosenthal, N. E. (2016). Emotional proprioception: treatment of depression with afferent facial feedback. Journal of psychiatric research, 80, 93-96. DOI: 10.1016/j.jpsychires.2016.06.009

Finzi, E., & Wasserman, E. (2006). Treatment of depression with botulinum toxin A: a case series. Dermatologic Surgery, 32(5), 645-650. DOI: 10.1111/j.1524-4725.2006.32136.x

Hennenlotter, A., Dresel, C., Castrop, F., Ceballos-Baumann, A. O., Wohlschläger, A. M., & Haslinger, B. (2008). The link between facial feedback and neural activity within central circuitries of emotion—New insights from Botulinum toxin–induced denervation of frown muscles. Cerebral Cortex, 19(3), 537-542. DOI: 10.1093/cercor/bhn104

Kim, M. J., Neta, M., Davis, F. C., Ruberry, E. J., Dinescu, D., Heatherton, T. F., ... & Whalen, P. J. (2014). Botulinum toxin-induced facial muscle paralysis affects amygdala responses to the perception of emotional expressions: preliminary findings from an ABA design. Biology of mood & anxiety disorders, 4(1), 11. DOI: 10.1186/2045-5380-4-11

Magid, M., Reichenberg, J. S., Poth, P. E., Robertson, H. T., LaViolette, A. K., Kruger, T. H., & Wollmer, M. A. (2014). Treatment of major depressive disorder using botulinum toxin A: a 24-week randomized, double-blind, placebo-controlled study. The Journal of clinical psychiatry, 75(8), 837-844. DOI: 10.4088/JCP.13m08845

Magid, M., Finzi, E., Kruger, T. H. C., Robertson, H. T., Keeling, B. H., Jung, S., ... & Wollmer, M. A. (2015a). Treating depression with botulinum toxin: a pooled analysis of randomized controlled trials. Pharmacopsychiatry, 25(06), 205-210. DOI: 10.1055/s-0035-1559621

Magid, M., Finzi, E., Kruger, T. H. C., Robertson, H. T., Keeling, B. H., Jung, S., ... & Wollmer, M. A. (2015b). Treating depression with botulinum toxin: a pooled analysis of randomized controlled trials. Pharmacopsychiatry, 48(6), 205-210. DOI: 10.1055/s-0035-1559621

Wollmer, M. A., de Boer, C., Kalak, N., Beck, J., Götz, T., Schmidt, T., ... & Sönmez, D. (2012). Facing depression with botulinum toxin: a randomized controlled trial. Journal of psychiatric research, 46(5), 574-581. DOI: 10.1016/j.jpsychires.2012.01.027

Answer 1

With the decrease in amygdala activity in response to angry faces, am I correct in thinking that this could have a detrimental effect with regard to the flight/flight response in potentially dangerous situations?

Yes, but like everything in neuroscience, it's probably more complicated that that. Working back from first principles, the same could be said of other antidepressant treatments:

Antidepressant Drug Treatment Modifies the Neural Processing of Nonconscious Threat Cues

Background The amygdala is believed to play a key role in processing emotionally salient, threat-relevant, events that require further online processing by cortical regions. Emotional disorders such as depression and anxiety have been associated with hyperactivity of the amygdala, but it is unknown whether antidepressant treatment directly affects amygdala responses to emotionally significant information.

Methods The current study assessed the effects of 7 days administration of the selective serotonin reuptake inhibitor (SSRI), citalopram, on amygdala responses to masked presentations of fearful and happy facial expressions in never-depressed volunteers using blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging. A double-blind, between-groups design was used with volunteers randomized to 20 mg/day citalopram versus placebo.

Results Volunteers receiving citalopram showed decreased amygdala responses to masked presentations of threat compared with those receiving placebo. Citalopram also reduced responses within the hippocampus and medial prefrontal cortex (mPFC) specifically during the fear-relevant stimuli. These neural differences were accompanied by decreased recognition of fearful facial expressions assessed after the scan. By contrast, there was no effect of citalopram on the neural or behavioral response to the happy facial expressions.

Conclusions These results suggest a direct effect of serotonin potentiation on amygdala response to threat-relevant stimuli in humans. Such effects may be important in the therapeutic actions of antidepressants in depression and anxiety.

Maybe perceiving the world as less threatening is precisely what depressed people need in their lives. However, there may be something more interesting at play with respect to botox. In the papers you cite, these all have to do with interpretation of facial expressions. For example, in Hennenlotter et al. 2009:

The Link between Facial Feedback and Neural Activity within Central Circuitries of Emotion—New Insights from Botulinum Toxin–Induced Denervation of Frown Muscles

Afferent feedback from muscles and skin has been suggested to influence our emotions during the control of facial expressions. Recent imaging studies have shown that imitation of facial expressions is associated with activation in limbic regions such as the amygdala. Yet, the physiological interaction between this limbic activation and facial feedback remains unclear. To study if facial feedback effects on limbic brain responses during intentional imitation of facial expressions, we applied botulinum toxin (BTX)–induced denervation of frown muscles in combination with functional magnetic resonance imaging as a reversible lesion model to minimize the occurrence of afferent muscular and cutaneous input. We show that, during imitation of angry facial expressions, reduced feedback due to BTX treatment attenuates activation of the left amygdala and its functional coupling with brain stem regions implicated in autonomic manifestations of emotional states. These findings demonstrate that facial feedback modulates neural activity within central circuitries of emotion during intentional imitation of facial expressions. Given that people tend to mimic the emotional expressions of others, this could provide a potential physiological basis for the social transfer of emotion.

If the mechanism of action of botox involves facial proprioception and there's a reduced amygdalar response to angry or fearful facial expressions, I would speculate that this involves mirror neurons in some manner.

Without the administration of botox, an interesting experiment would be examine the threat perception of facial expressions in people with a forced grin. We would also predict that threat perception is still present when other threatening stimuli are used e.g. handgun. I'm sure it's been done by someone.